Nucleoside analogues are molecules that act like or mimic natural nucleosides in DNA synthesis. Compounds within the category “nucleoside analogs” are important therapeutic agents for the treatment of cancer, viral infection and immunosuppressive disorders. Nucleoside analogs exert their therapeutic effect by inhibiting DNA synthesis. After entry into a cell, nucleoside analogs are phosphorylated to the corresponding mono-, di-, or triphosphates. Triphosphate nucleoside analogs inhibit cell division by terminating DNA transcription.
Nucleoside analogs also have a well-established regulatory history, with several nucleoside analogs currently approved by the US Food and Drug Administration (FDA) for the treatment of diseases, such as human immunodeficiency virus (HIV) infection, hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection and cancer.
The hepatitis B virus (HBV) is second only to tobacco as a cause of human cancer. The mechanism by which HBV induces cancer is unknown. It is postulated that HBV infection may directly trigger tumor development, or indirectly trigger tumor development through chronic inflammation, cirrhosis, and cell regeneration associated with the infection. Persons infected by HBV suffer from acute hepatitis and liver damage, resulting in abdominal pain, jaundice and elevated blood levels of certain liver enzymes. While patients typically recover from acute HBV infection, the virus can continue to replicate indefinitely causing a chronic persistent hepatitis which is one of the main causes of hepatocellular carcinoma, a primary liver cancer.
3TC (lamivudine), interferon alpha-2b, peginterferon alpha-2a, hepsera (adefovir dipivoxil), baraclude (entecavir), and Tyzeka (Telbivudine) are currently FDA-approved drugs for treating HBV infection. However, many of these drugs have severe side effects and viral resistance develops rapidly in patients treated with these drugs. Other disadvantages of commercially available nucleoside analogs include without limitation the difficulty associated with their manufacture utilizing multi-step synthetic protocols that require time-consuming, costly purification, as well as challenges associated with their stability during storage and the ability to inhibit viral replication without damaging the host cells.